ANTITHROMBIN ACTS AS A NEGATIVE ACUTE-PHASE PROTEIN AS ESTABLISHED WITH STUDIES ON HEPG2 CELLS AND IN BABOONS

Patients with sepsis or after major surgery have decreased plasma leve ls of the anticoagulant protein antithrombin. In such patients elevate d levels of interleukin-6 (IL-6) are present and this interleukin is k nown to induce positive and negative acute phase responses. To investi gate the possibility that antithrombin acts as a negative acute phase response-protein we performed studies on the human hepatoma cell line HepG2 in vitro and baboons in vivo. HepC2 cells were treated with reco mbinant human IL-6, IL-1 beta or combinations of the latter two, and t ested for production of antithrombin, fibrinogen and prealbumin (trans thyretin). This treatment resulted in a dose dependent increase in fib rinogen concentration (with a maximum effect of 2.8-2.9-fold) and a do se dependent decrease in prealbumin (with a maximum effect of 0.6-0.7- fold)! and antithrombin concentrations (with a maximum effect of 0.6-0 .8-fold). Simultaneous treatment of the HepG2 cells with IL-6 (1,000 p g/ml or 2,500 pg/ml) and IL-1 beta (25 pg/ml), provided more extensive ly decreased prealbumin (0.8 and 0.6-fold, respectively) and antithrom bin concentration (0.7 and 0.6-fold, respectively) compared to the sin gle interleukin treatment at these concentrations. Baboons treated wit h 2 mu g IL-6 kg body-weight(-1).day(-1) showed increased plasma CRP l evels (59-fold, p < 0.05) and decreased prealbumin (0.9-fold, p < 0.05 ) and antithrombin (0.8-fold, p < 0.05) plasma levels, without evidenc e for coagulation activation. Our results indicate that antithrombin a cts as a negative acute phase protein, which may contribute to the dec reased antithrombin plasma levels observed after major surgery or in s epsis.